The hippocampus is a brain region of central importance to cognitive functions such as learning and memory. Historically, information processing in the hippocampus has been examined in the context of a series of three pathways called the trisynaptic circuit. The first step involves entorhinal cortical activation of granule cells, and the second step involves granule cell activation of area CA3 pyramidal cells. Increased awareness of hippocampal anatomy and physiology has led to the suggestion that the trisynaptic circuit needs to be considered in light of other hippocampal pathways in order to understand hippocampal signal processing more completely. One reason is that the axon collaterals of the granule cells not only innervate pyramidal cells, but also traverse the adjacent hilar region, where they innervate hilar neurons. Granule cells activate both classes of hilar neurons, the glutamatergic "mossy cells" and GABAergic "interneurons," each of which in turn innervate granule cells, and possibly other neurons as well. Despite these potentially important connections, the full extent of synaptic interactions of hilar neurons with other hippocampal neurons is presently unclear. This proposal outlines experiments to characterize hilar synapses with granule cells, pyramidal cells, and other hilar neurons, and test whether hilar neurons influence activation of granule cells and pyramidal cells within the context of the trisynaptic circuit. Both low frequency and high frequency activation will be considered, in order to interpret conditions of sparse input to the hippocampus and conditions which may lead to potentiation of hippocampal circuits. The goal is to understand how hilar neurons may influence information flow from the dentate gyrus to area CA3, and to elucidate the role of hilar cells in plasticity involving the dentate gyrus-CA3 network. To achieve these goals, electrophysiological and voltage-imaging techniques will be used in parallel. The results will provide insight into cognitive function that should ultimately help in the understanding and treatment of learning disorders and mental illness.